The long-term objective of this study is to identify genes involved in the risk of bipolar disorder Starting in 1993, in collaboration with 10 academic centers across the United States, we recruited a large sample of over 3,000 individuals with BD or related mood disorders. This is the largest sample ever to participate in a genetic study of BD. All participants did a diagnostic interview and provided a blood sample for DNA analysis. DNA and clinical data are available through the NIMH Center for Genetics. Genetic linkage studies suggested several chromosomal regions may contain genes that contribute to BD in this sample. To identify individual causal genes, we conducted the first genome-wide association study of BD in 2007. The results implicated several genes, each of small effect, suggesting that bipolar disorder is a polygenic disease. Our recent meta-analysis of independent case-control studies of bipolar disorder supported association with a cluster of genes on chromosome 3p21, TRANK1, LMAN2L, and PTGFR, and 2 independent regions of ANK3 implicated in previous studies. We have shown that models based on large numbers of markers can distinguish between cases and controls in independent datasets with high significance, but only modest predictive value. These studies also suggest that common alleles predisposing to BD also predispose to major depression and schizophrenia, but not to neurological diseases such as Parkinson Disease. To identify genetic variants that may have a much larger impact on individual risk, we have undertaken genome sequencing studies in selected populations, such as the Amish in Midwest. In this population, large families increase the opportunities for ascertaining distant relatives with BD, and individuals belonging to different nuclear families are often related, forming an extended kindred ideal for genome sequencing studies. So far we have collected about 100 ndividuals from Amish communities in Ohio and Indiana. Genotype analysis with common genetic markers helps allows us to establish genetic relationships and identify chromosomal regions that are shared in common among many cases. Exome sequencing has been completed on 22 individuals; additional cases and controls will be sequenced in the coming year. Finally, we are also searching for genetic markers that might help predict an individual's response to lithium, one of the most effective current treatments for BD. To this end, we organized a large international collaboration, known as the Consortium on Lithium Genetics (ConLiGen), which aims to characterize lithium response in a large group of patients using reliable instruments, then perform a genome-wide association study. So far we have perforemd a GWAS on over 1000 cases. Preliminary results suggest that additional samples will be needed to detect robust markers that pass all statistical tests.